Protein Phosphatase 2A Mediates Dormancy of Glioblastoma Multiforme-Derived Tumor Stem-Like Cells during Hypoxia 英文参考文献.docVIP

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Protein Phosphatase 2A Mediates Dormancy of Glioblastoma Multiforme-Derived Tumor Stem-Like Cells during Hypoxia 英文参考文献.doc

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Protein Phosphatase 2A Mediates Dormancy of Glioblastoma Multiforme-Derived Tumor Stem-Like Cells during Hypoxia 英文参考文献

ProteinPhosphatase2AMediatesDormancyof GlioblastomaMultiforme-DerivedTumorStem-LikeCells duringHypoxia ChristophP.Hofstetter1*,Jan-KarlBurkhardt1,BenjaminJ.Shin1,DemirkanB.Gu¨rsel1,LynnMubita1, RamanaGorrepati1,CameronBrennan2,EricC.Holland2,JohnA.Boockvar1 1Department of Neurological Surgery, Weill Cornell Brain Tumor Center, Weill Cornell Medical College, New York Presbyterian Hospital,New York, New York, United StatesofAmerica,2DepartmentofNeurosurgeryandDepartmentofCancerBiologyandGenetics,MemorialSloan-KetteringCancerCenter,NewYork,NewYork,United StatesofAmerica Abstract Purpose: The hypoxic microenvironment of glioblastoma multiforme (GBM) is thought to increase resistance to cancer therapies.Recentevidencesuggeststhathypoxiainducesproteinphosphatase2A(PP2A),aregulatorofcellcycleandcell death.TheeffectsofPP2AonGBMtumorcellproliferationandsurvivalduringhypoxicconditionshavenotbeenstudied. ExperimentalDesign:ExpressionofPP2AsubunitsandHIF-aproteinswasmeasuredin65high-gradeastrocytomaand18 non-neoplasticsurgicalbrainspecimensbywesternblotting.PP2Aactivitywasmeasuredbyanimmunoprecipitationassay. Forinvitroexperiments,GBM-derivedtumorstemcell-likecells(TSCs)wereexposedtoseverehypoxiaproducedbyeither CoCl2or1%O2.PP2AactivitywasinhibitedeitherbyokadaicacidorbyshRNAdepletionofthePP2ACsubunit.Effectsof PP2Aactivityoncellcycleprogressionandcellsurvivalduringhypoxicconditionswereassessedusingflowcytometry. Results:Inourpatientcohort,PP2AactivitywaspositivelycorrelatedwithHIF-1/proteinexpression(P=0.002).Patients with PP2A activity levels above 160 pMP had significantly worse survival compared to patients with levels below this threshold(P=0.002).PP2Aactivitywasanindependentpredictorofsurvivalonmultivariableanalysis(P=0.009).Inourin vitroexperiments,weconfirmedthatseverehypoxiainducesPP2AactivityinTSCs6hoursafteronsetofexposure.PP2A activity mediated G1/S phase growth inhibition and reduced cellular ATP consumption in hypoxic TSCs. Conversely, inhibition of PP2A activit